Project Summary Despite advances in anti-androgen and taxane-based therapies, prostate cancer (PC) often becomes castration-resistant, metastatic, and incurable. Consequently, there is an urgent need to develop novel interventions to treat metastatic PC. Lipid signaling and metabolism are major drivers of PC metastasis and present ideal targets for therapeutic intervention. However, therapeutic exploitation of lipid signaling systems is hampered by the existence of multiple lipid metabolizing enzymes and nuclear receptors, which would necessitate targeting these systems in parallel. Fatty acid binding protein 5 (FABP5) is an intracellular carrier that shuttles bioactive lipids to nuclear receptors, thereby activating gene transcription programs that enhance tumor growth and metastasis. FABP5 is not expressed in the normal prostate but becomes highly upregulated in advanced metastatic PC. Our group has obtained preliminary data demonstrating that FABP5 is indispensable for the delivery of pro-tumorigenic lipids produced by multiple cytosolic to nuclear receptors to promote PC metastasis. This positions FABP5 as an essential node in a PC lipid signaling network and an attractive target for the development of therapeutics to treat metastatic PC. Despite the considerable promise of FABP5 inhibitors as potential PC therapeutics, potent and selective inhibitors have yet to emerge. The major goal of this proposal is to develop and optimize novel potent and selective FABP5 inhibitors. The proposed multidisciplinary project will be carried out by a highly qualified team with expertise in computer-aided drug design, medicinal chemistry, and PC biology. Aim 1 will leverage structure-based drug design and iterative chemical synthesis approaches to identify and optimize FABP5 inhibitors for potency and selectivity. Aim 2 will employ a robust in vitro inhibitor testing platform including assessments of inhibitor potency, efficacy, selectivity, stability, and cytotoxicity in PC cell-lines and non-transformed cells. Aim 3 will assess the efficacy of candidate inhibitors in mouse models of PC, including a novel genetically engineered mouse model of androgen-dependent and castration-resistant PC. We will also assess the efficacy of FABP5 inhibitors when used as monotherapies and in combination with FDA approved therapeutics. Successful completion of the proposed studies will lead to the development of optimized FABP5 inhibitor scaffolds that can be advanced to late stage IND-enabling studies and eventual clinical deployment.